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Cited by 206Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersGenetic Associations and Epidemiology

A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex

Open access
Antaki, Danny, Guevara, James, Maihofer, Adam X., Klein, Marieke, Gujral, Madhusudan, Grove, Jakob, Carey, Caitlin E., Hong, Oanh +12 more·2022·Nature Genetics
DOI 10.1038/s41588-022-01064-5PMC PMC9474668

Published version of a preprint

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Abstract

The genetic etiology of autism spectrum disorder (ASD) is multifactorial, but how combinations of genetic factors determine risk is unclear. In a large family sample, we show that genetic loads of rare and polygenic risk are inversely correlated in cases and greater in females than in males, consistent with a liability threshold that differs by sex. De novo mutations (DNMs), rare inherited variants and polygenic scores were associated with various dimensions of symptom severity in children and parents. Parental age effects on risk for ASD in offspring were attributable to a combination of genetic mechanisms, including DNMs that accumulate in the paternal germline and inherited risk that influences behavior in parents. Genes implicated by rare variants were enriched in excitatory and inhibitory neurons compared with genes implicated by common variants. Our results suggest that a phenotypic spectrum of ASD is attributable to a spectrum of genetic factors that impact different neurodevelopmental processes.

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Crossref · 10.1038/s41588-022-01064-5

Cites

83 of 83 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 29 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    ASD cases carrying damaging de novo mutations had a lower combined polygenic load than cases without damaging DNMs.

    “cases who carry de novo damaging mutations (dnLoF or dnMIS) had a combined polygenic load that was reduced compared to cases that do not carry damaging DNMs (Fig. 4).”
    Quote in the paperSubstantial claim
  • Findingown data

    The combined contribution of rare variants also explained 2% of the variance in ASD case status.

    “The combined contribution of rare variants was similar, also explaining 2% of the variance in case status (Fig. 2a).”
    Quote in the paperSubstantial claim
  • Findingown data

    The additive effects of all six genetic factors combined explained 4% of the variance in ASD case status.

    “the additive effects of all factors combined could be quantified in a single model (r2 = 4%, Fig. 2a and Supplementary Table 12).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The genetic factors combine additively to determine ASD liability.
  • Findingown data

    Rare inherited protein-truncating SNVs and structural variants are associated with ASD.

    “TDT confirmed the associations of rare inherited protein-truncating SNVs (inhLoF) and SVs (LoFSV) (Fig. 1b and Supplementary Tables 7–9).”
    Quote in the paperSubstantial claim
  • Findingown data

    Rare inherited loss-of-function variants were negatively correlated with DNMs (P = 0.03).

    “rare inherited variants (inhLoF) were negatively correlated with DNMs (P = 0.03; Extended Data Fig. 2a).”
    Quote in the paperSubstantial claim
  • May combine two claims. 40
  • Classified as probably not a substantial claim. 12
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    The composite rare-variant and common-variant risk scores were negatively correlated (P = 0.0037, Pearson correlation = −0.015), and this correlation was stronger than the pairwise correlations of individual factors.

    “The negative correlation of the composite risk scores RVRS and CVRS (P = 0.0037, Pearson correlation = −0.015) was stronger than for the pairwise correlations of individual factors (Fig. 4b and Supplementary Table 15)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The genetic factors combine additively to determine ASD liability.

  • May combine two claims.

    Findingown data

    Structural variants disrupting cis-regulatory regions of constrained genes showed differential transmission in cases and controls, but the TDT test was not statistically significant in cases.

    “SVs that disrupt cis-regulatory variants (CRE-SVs) of constrained genes showed differential transmission in cases and controls, but the TDT test did not reach statistical significance in cases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Polygenic scores for ASD, schizophrenia, and educational attainment are each significantly associated with ASD.

    “Polygenic scores PSASD, PSSZ and PSEA were all significantly associated with ASD (Fig. 1c and Supplementary Table 10)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The genomic risk score distribution is bimodal, with a subset of DNM carriers having the highest scores and the greatest enrichment of female cases.

    “As expected, the distribution of GRS is bimodal, with a subset of DNM carriers having the highest scores and the greatest enrichment of female cases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Eleven gene-trait relationships showed nominal evidence for interaction by sex, but none remained significant after correction for multiple testing.

    “Eleven gene-trait relationships showed nominal evidence for an interaction by sex, but none were statistically significant after correction for multiple testing.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    PSASD was associated with social deficits, while dnLoF was correlated with reduced symptom severity in parents.

    “with PSASD associated with social deficits and dnLoF correlated with reduced symptom severity in parents consistent with a de novo etiology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Sex differences in genetic effects were not exclusively male-biased; 5 of 11 had stronger effects in females.

    “Sex-differences in genetic effects were not exclusively male-biased (5/11 had stronger effects in females).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Parents' education levels were significantly correlated with parental age and were maternally biased (r2 maternal = 0.066, paternal = 0.023).

    “parents’ levels of education were significantly correlated with parental age in our sample and maternally biased (r2maternal = 0.066, r2paternal = 0.023)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Six gene-trait correlations were significant after Bonferroni correction for 72 tests, and 18 showed nominal associations.

    “Six gene-trait correlations were significant after Bonferroni correction for 72 tests (Fig. 5a), and 18 showed nominal associations (P ≤ 0.05).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Deficits in motor coordination were associated with rare variants (dnMIS, dnLoF, inhLoF) but not with polygenic scores.

    “Deficits in motor coordination (DCDQ) were associated with rare variants (dnMIS, dnLoF, inhLoF) but not with polygenic scores.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The strongest inherited factor influencing parental age was PSEA (r2 = 0.017), while PSASD and PSSZ showed much weaker correlations (r2 ≤ 0.0006).

    “The single strongest inherited factor that influenced parental age was PSEA (r2 = 0.017; Supplementary Table 17), while PSASD and PSSZ showed much weaker correlations (r2 ≤ 0.0006).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Social deficits in offspring were associated with polygenic risk for ASD and de novo loss-of-function mutations, and the same factors influenced social behavior in parents.

    “Social deficits (SCQ, SRS) in offspring were associated with polygenic risk (PSASD) and de novo mutations (dnLoF), and the same factors influenced social behavior (SRS, BAPQ) in parents (Fig. 5b)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The rate of de novo SNVs increased with paternal age (r2 = 0.42) and maternal age (r2 = 0.27).

    “the rate of de novo SNVs increased with paternal age in the combined dataset (r2paternal = 0.42, r2maternal = 0.27; Extended Data Fig. 4)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    PSEA was protective for repetitive behavior and social communication deficits in offspring and was associated with reduced symptom severity in parents.

    “PSEA was protective for core ASD symptoms of repetitive behavior (RBS) and social communication deficits (SCQ) in offspring and was also associated with reduced symptom severity in parents (BAPQ, EA).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Common PSEA and rare inhLoF variation in fathers were associated with older and younger paternal age, respectively.

    “common (PSEA) and rare (inhLoF) variation in fathers were associated with older and younger paternal age respectively (Fig. 6a)”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Multiple inherited genetic factors in parents (inhLoF, PSEA, PSSZ) were associated with parental age.

    “multiple inherited genetic factors in parents (inhLoF, PSEA, PSSZ) were associated with parental age.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In bulk human cortex, GWAS genes were more highly expressed than the null distribution, and TADA genes were further enriched.

    “In bulk human cortex, GWAS genes were more highly expressed (expression across all cortex samples and periods) compared to the null distribution, and TADA genes were further enriched (Fig. 7a).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Rare inhLoF variants were associated with early paternal age, and fathers carrying inhLoFs had reduced educational attainment, but this association was not statistically significant (P < 0.058).

    “Rare inhLoF variants were associated with early paternal age, and fathers that carried inhLoFs had reduced educational attainment, but this association was not statistically significant (P < 0.058; Supplementary Table 18).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    After normalizing cortex expression across periods, GWAS genes showed increased relative expression during fetal development compared with the null, and TADA genes showed further enrichment in fetal cortex.

    “After normalizing cortex expression of each gene across periods, GWAS genes show increased relative expression during fetal development (Fig. 7b) compared to the null, and again TADA genes showed a further enrichment in fetal cortex.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Genetic effects on social communication in cases consisted of two factors with male bias (PSASD and PSSZ) and two with female bias (inhLoF and PSEA).

    “Genetic effects on social communication in cases consisted of two factors with evidence of a male bias (PSASD and PSSZ) and two with evidence of a female bias (inhLoF and PSEA).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Parental education and parental age were significantly correlated, more strongly for mothers (r2 = 0.06, P = 3.5 × 10−52) than fathers (r2 = 0.03, P = 1.3 × 10−23).

    “We confirmed in our dataset a significant correlation of parental education and parental age47 that was stronger for mothers (r2 = 0.06, P = 3.5 × 10−52; Supplementary Table 19) than for fathers (r2 = 0.03, P = 1.3 × 10−23).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Boyle, E. A., Li, Y. I. & Pritchard, J. K. An expanded view of complex traits: from polygenic to omnigenic. Cell 169, 1177–1186 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    PSEA was negatively correlated with symptom severity in offspring and parents but positively correlated with case status.

    “The one exception was PSEA, which was negatively correlated with symptom severity in offspring and parents but was positively correlated with case status.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The predictive accuracies of polygenic scores and rare variants were similar, each explaining 2% of variance in case status.

    “In this study, the predictive accuracies of polygenic scores and rare variants were similar, each explaining 2% of variance in case status.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Genes implicated by rare variants were more strongly enriched during fetal development, specifically within neurons, compared with genes implicated by common variants.

    “genes implicated by rare variants were more strongly enriched during fetal development, specifically within neurons.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At the level of cortical cell types, TADA gene expression was about twofold greater than the null in excitatory and inhibitory neurons, while GWAS genes did not show significant enrichment by cell type.

    “At the level of cortical cell types, the expression of TADA genes was significantly (~2 fold) greater than the null in excitatory and inhibitory neurons (Fig. 7c and Supplementary Table 21), and GWAS genes did not show a significant enrichment of expression by cell type.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Multiple genetic factors were associated with parental age, with effects that differed by sex.

    “Multiple genetic factors were associated with parental age with effects that differed by sex.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Multiple genetic factors influence ASD symptom severity in cases and in their typically developing siblings and parents, with each factor having a different pattern of trait association.

    “Multiple genetic factors influence ASD symptom severity in cases and in their typically developing siblings and parents, with each factor having a different pattern of trait-association.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both maternal and paternal rare variants contribute to ASD, with significant over-transmission from mother to daughter and from father to son.

    “Both maternal and paternal rare variants contribute to ASD with a significant over-transmission from mother to daughter and from father to son.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    In the SPARK cohort, there was a 1.1-fold excess of synonymous variants in cases (OR=1.1, P=0.02).

    “In the SPARK cohort we observed a 1.1-fold excess of synonymous variants in cases (OR = 1.1, P = 0.02).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    A significant liability threshold for rare variants was evident from a negative correlation between dnLoF and inhLoF (linear regression P=0.03), and this effect did not differ significantly by sex.

    “A significant liability threshold for rare variants was evident based on a negative correlation of dnLoF and inhLoF (linear regression P = 0.03), and this effect did not differ significantly by sex.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    With SBayesR polygenic scores, there was a similar trend of a stronger CVRS-RVRS correlation in males, but the gene-by-sex interaction was not statistically significant.

    “With polygenic scores calculated using SBayesR, there was a similar trend with the correlation of CVRS and RVRS being stronger in males; however, the gene-by-sex interaction was not statistically significant.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    An early analysis using PRSice found that the negative correlation between RVRS and CVRS was stronger in males than in females.

    “An early analysis of this dataset using polygenic score estimates from PRSice observed that the negative correlation of RVRS and CVRS was stronger in males than in females, consistent with males having less tolerance of genetic risk.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    ASD risk is influenced by both rare and common genetic variants, including de novo CNVs, large-effect protein-truncating SNPs and indels, and common polygenic risk made up of many small-effect alleles.

    “The major risk factors for autism spectrum disorder (ASD) are genetic and include a variety of rare and common alleles, including rare de novo copy number variants (CNVs)1 or protein-truncating SNPs and indels of large effect2 and common polygenic risk that is measured as the sum of thousands of common alleles with small effects3.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1] Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007). source

      Not checked in the free run.

    • cites [2] Iossifov, I. et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515, 216–221 (2014). source

      Not checked in the free run.

    • cites [3] Grove, J. et al. Identification of common genetic risk variants for autism spectrum disorder. Nat. Genet. 51, 431–444 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The findings are consistent with a female protective effect in which females tolerate a greater load of ASD risk alleles and need a greater genetic load to meet diagnostic criteria.

    “These results are consistent with a “female protective effect” in which females in the general population tolerate a greater genetic load of ASD risk, and likewise a greater genetic load is required for females to meet diagnostic criteria for ASD case status21.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Werling, D. M. The role of sex-differential biology in risk for autism spectrum disorder. Biol. Sex. Differ. 7, 58 (2016). source

      Not checked in the free run.

    • The authors state this as an assumption: ASD liability follows a threshold model in which total genetic load determines whether an individual meets diagnostic criteria.

  • Classified as probably not a substantial claim.

    Premisecitation

    Females with ASD have a greater burden of rare CNVs and gene mutations than males with ASD.

    “This hypothesis is supported by previous studies showing that females with ASD have a greater burden of rare CNVs1,11,12 and gene mutations13,14.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [1] Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007). source

      Not checked in the free run.

    • cites [11] Sanders, S. J. et al. Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron 87, 1215–1233 (2015). source

      Not checked in the free run.

    • cites [12] Desachy, G. et al. Increased female autosomal burden of rare copy number variants in human populations and in autism families. Mol. Psychiatry 20, 170–175 (2015). source

      Not checked in the free run.

    • cites [13] Jacquemont, S. et al. A higher mutational burden in females supports a ‘female protective model’ in neurodevelopmental disorders. Am. J. Hum. Genet. 94, 415–425 (2014). source

      Not checked in the free run.

    • cites [14] De Rubeis, S. et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515, 209–215 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The genetic architecture of ASD varies along a spectrum of rare and common variation, with distinct phenotypic correlates and different effects in males and females.

    “We show that the genetic architecture of ASD varies as a spectrum of rare and common variation, each having distinct phenotypic correlates and differential effects in males and females.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The genetic architectures of ASD vary across cases, as shown by an inverse correlation of rare variants and polygenic scores, consistent with a liability threshold model.

    “The genetic architectures of ASD vary across cases, which is evident by an inverse correlation of rare variants and polygenic scores, consistent with a liability threshold model.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: ASD liability follows a threshold model in which total genetic load determines whether an individual meets diagnostic criteria.
    • Rests on an assumption: The genetic factors combine additively to determine ASD liability.

  • May combine two claims.

    Interpretationown data

    Female cases have a significantly greater overall genetic load of polygenic and rare variation than male cases, confirming that a female protective effect applies generally to all components of the genetic architecture.

    “female cases have a significantly greater overall genetic load of polygenic and rare variation than male cases, confirming that a “female protective effect”, in which females display a greater tolerance for ASD risk alleles, applies generally to all components of the genetic architecture.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: ASD liability follows a threshold model in which total genetic load determines whether an individual meets diagnostic criteria.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Analysis was restricted to 7,181 families with confirmed European ancestry to minimize ancestry as a confounder in polygenic scores.

    “To minimize ancestry as a confounder in PSs, analysis was restricted to a subset of 7,181 families (n = 25,391 individuals) with parents and offspring that have confirmed European ancestry.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The polygenic TDT test had previously demonstrated overtransmission of PSASD, PSSZ and PSEA to cases, establishing proof of concept for including these scores in this study.

    “For this reason, these polygenic scores were selected for the first family-based study that applied a polygenic TDT test (also used in this study) to demonstrate an overtransmission of PSASD, PSSZ and PSEA to cases17. This established for us the proof of concept for their inclusion in this study.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Weiner, D. J. et al. Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders. Nat. Genet. 49, 978–985 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The research complied with relevant ethical regulations and was approved by the UC San Diego School of Medicine IRB.

    “Our research complies with all relevant ethical regulations as approved by the institutional review board (IRB) of the UC San Diego School of Medicine.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    In SPARK, de novo SNV calls had a recall of 92.6-98.2% (n=117) and de novo indel calls had a recall of 98.6-100% (n=107) against Sanger-validated DNMs from a previous pilot study.

    “For SNVs, the recall rate for SNVs ranged from 92.6% to 98.2% (n = 117), while for indels the recall range from 98.6 to 100% (n = 107).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Antaki, D., Brandler, W. M. & Sebat, J. SV2: accurate structural variation genotyping and de novo mutation detection from whole genomes. Bioinformatics 34, 1774–1777 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    No variables could be identified that explain the subtle baseline difference in dnSyn burden in SPARK, so none could be included as covariates in a regression model.

    “Thus, variables could not be identified that explain a subtle baseline difference in dnSyn burden, which could be included as covariates in a regression model.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Overall results were highly consistent between the two polygenic scoring methods.

    “overall results were highly consistent between both PS methods.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Among the polygenic scoring methods evaluated, the method with the greatest prediction accuracy for ASD case status was selected for all analyses.

    “Two polygenic scoring methods were evaluated, and the method with the greatest prediction accuracy for ASD case status was selected for all analyses described here.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    For the SPARK exome dataset, DNMs were retained only when at least three of five classifiers called them, a rule intended to maximize sensitivity while controlling false positives.

    “To maximize sensitivity while controlling for false positives, we retained DNMs if they were called by three out of the five classifiers.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    Genetic effects were tested by linear regression controlling for cohort, age, sex, and principal components, and gene-by-sex interactions were also tested.

    “Genetic effects were tested by linear regression controlling for cohort, age, sex and principal components, and effects were also tested for gene-by-sex interactions (Supplementary Table 17).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The subtle dnSyn excess in SPARK does not bias the combined sample and cannot explain the strong associations reported for other de novo mutation categories.

    “However, this very subtle effect does not contribute to a bias in the combined sample and cannot explain the strong associations reported for other categories of de novo mutation (Fig. 1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    The stronger negative correlation between RVRS and CVRS in males is consistent with males having less tolerance of genetic risk.

    “consistent with males having less tolerance of genetic risk.”
    Quote in the paperNot a substantial claim
49 of 49

  • The paper relies on this without support.

    No single variant, gene, or polygenic score has high predictive value for an ASD diagnosis.

    “Despite the success in identifying and characterizing multiple types of genetic risk, there is no one variant, gene or polygenic score (PS) that has a high predictive value for an ASD diagnosis.”

  • The paper relies on this without support.

    Males are diagnosed with ASD more frequently than females at a ratio of 4:1.

    “Males are diagnosed with ASD more frequently than are females at a ratio of 4:1.”

  • The paper relies on this without support.

    Gene-by-sex interactions in ASD have not been examined systematically.

    “However, gene-by-sex interactions in ASD have not been examined systematically.”

  • The paper relies on this without support.

    How combinations of multiple genetic factors contribute to ASD risk and clinical presentation is not known.

    “How combinations of multiple genetic factors contribute to risk and clinical presentation is not known.”

  • The authors state this as an assumption.

    ASD liability follows a threshold model in which total genetic load determines whether an individual meets diagnostic criteria.

    “According to a liability-threshold model for ASD22,23, a total genetic load sufficient to meet diagnostic criteria can be reached through differing combinations of rare and common variation.”

  • The paper relies on this without support.

    The genetic factors combine additively to determine ASD liability.

    “consistent with liability being attributable to the additive effects of multiple rare and common genetic factors.”

  • The paper relies on this without support.

    Many de novo CNV calls from microarrays in SSC samples are likely to be missed by paired-end SV callers.

    “since many of these calls are likely to be missed by paired-end SV callers.”

  • The paper relies on this without support.

    PSSZ and PSEA are among the most well-powered GWASs.

    “but they are among the most well powered GWASs.”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Autistic females are more likely than autistic males to carry a higher burden of de novo rare variants, which is inversely related to polygenic score load.

    “Autistic females are also more likely than autistic males to carry a higher burden of de novo rare variants235,236, which is inversely related to polygenic score load236.”

    From Sex and gender in neurodevelopmental conditions (2023) · cites this paper as [236]

  • Studies investigating the female protective effect in autism have used partly overlapping samples, and independent replication is therefore required.

    “Studies investigating the so-called female protective effect in autism have used partly overlapping samples, and independent replication is therefore required225,227–229,236.”

    From Sex and gender in neurodevelopmental conditions (2023) · cites this paper as [236]

  • Existing studies investigating genotype-phenotype associations have been limited to summed scores of core autism features in smaller sample sizes rather than underlying latent dimensions.

    “First, existing studies investigating genotype–phenotype associations have been limited to summed scores of core autism features in smaller sample sizes19–21 rather than the underlying latent dimensions.”

    From Genetic correlates of phenotypic heterogeneity in autism (2022) · cites this paper as [19]

  • Neither of these studies stratified by ID.

    “yet neither have stratified by ID.”

    From Genetic correlates of phenotypic heterogeneity in autism (2022) · cites this paper as [19]

  • Recent studies have found higher PGS for autism in females than in males.

    “Recent studies have found higher PGS for autism in females than in males19”

    From Genetic correlates of phenotypic heterogeneity in autism (2022) · cites this paper as [19]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • TADA gene-set size differs between Results and Methods

    Minor

    The Results report 125 TADA genes meeting the FDR threshold, whereas the Methods report 113 genes at the same threshold.

  • Reference genome used for initial alignment is stated inconsistently

    Minor

    The processing overview says all calls came from sequence aligned to GRCh38, but the REACH cohort description says its reads were aligned to GRCh37 before variant calls were lifted over.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Grove, J. et al. Identification of common genetic risk variants for autism spectrum disorder. Nat. Genet. 51, 431–444 (2019). · DOI · Paper page
  2. Brandler, W. M. et al. Paternally inherited cis-regulatory structural variants are associated with autism. Science 360, 327–331 (2018). · DOI · Paper page

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Authors
Antaki, D., Guevara, J., Maihofer, A. X., Klein, M., Gujral, M., Grove, J., Carey, C. E., Hong, O., Arranz, M. J., Hervas, A., Corsello, C., Vaux, K. K., Muotri, A. R., Iakoucheva, L. M., Courchesne, E., Pierce, K., Gleeson, J. G., Robinson, E. B., Nievergelt, C. M., & Sebat, J.
Affiliations
  • University of California San Diego (US)
  • Aarhus University (DK)
  • Broad Institute (US)
  • University Hospital Mútua de Terrassa (ES)
  • University of North Carolina at Chapel Hill (US)
  • Human Longevity (United States) (US)
Corresponding author
Sebat, Jonathan
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2022-06-02
Volume
54
Issue
9
Pages
1284-1292
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-022-01064-5
PMC
PMC9474668
OpenAlex
W4281713460
Semantic Scholar
0008b454a46a30b9f471497ac83e0073653ada2e
Cited by
206
References
83
Citations by year
2026: 36 · 2025: 50 · 2024: 56 · 2023: 40 · 2022: 22 · 2021: 1 · 2020: 1
FWCI
22.69
Type
journal article
Language
en
Update notices
correction (2022-06-29)
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • medRxiv (acceptedVersion, cc-by-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (MH119746, 1MH109501, MH113715, MH106595, MH109514)
  • Simons Foundation (SFARI 606768)
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (GM008666)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
autism spectrum disorder, rare variants, polygenic risk, de novo mutations, sex differences, parental age, polygenic risk score, symptom severity, excitatory and inhibitory neurons, brain development, family-based genetic study
MeSH terms
Autism Spectrum Disorder, Autistic Disorder, Child, Family, Female, Humans, Male, Genetic Predisposition to Disease, Multifactorial Inheritance

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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